Essential hypertension is a major threat to public health, affecting over a billion people in the world and contributing to kidney and cardiovascular mortality and morbidity in 5 million people annually. Like other complex disorders, multiple genes with variant alleles and different environmental stresses are thought to contribute to the disease. Using a genome-wide association strategy, we recently identified the first essential hypertension susceptibility gene, STK39 (aka SPAK serine/threonine kinase), illuminating a newly described, multi-gene kinase network and a specific environmental trigger--dietary salt-- in the genesis of hypertension. Available evidence from our group and others suggests: 1) STK39 interacts with the products of the WNK genes, serine/threonine kinases that are mutated in a rare familial disorder of hypertension and hyperkalemia, to control kidney salt excretion and maintain blood pressure;2) Dietary sodium and potassium differently trigger signaling through the STK39/WNK pathway to regulate the activity of a key renal salt transport protein, the thiazide diuretic sensitive sodium chloride co- transporter (NCC);3) Aberrant gain-of-STK39 signaling causes an inappropriate increase in NCC activity, leading to sodium retention and hypertension. Here we bring together a mutlidisciplinary team to develop and apply novel transgenic animal models and reagents to test these exciting new ideas about gene-gene and gene-environment interactions in the development of hypertension, building on our recent discoveries. Development of these new tools and knowledge will shed light on the underlying molecular and genetic mechanisms of the disease. It also will provide much-needed models to study and identify new therapeutic strategies for intervention. PUBLIC HEALTH RELEVANCE: Essential hypertension is a major threat to public health, affecting over a billion people in the world and contributing to kidney and cardiovascular mortality and morbidity in 5 million people annually. Like other complex disorders, multiple genes with variant alleles and different environmental stresses are thought to contribute to the disease. Here we bring together a mutlidisciplinary team of experts in the field to develop and apply novel transgenic animal models and reagents to test exciting new ideas about a multi-kinase gene network and a specific environmental trigger--dietary salt--in the genesis of hypertension, building on our recent GWA discovery of STK39 kinase as an essential hypertension susceptibility gene.